In addition to generating antibodies secreted by the B-cell population specific for epitopes associated with them and tumors, like other foreign substances, set in motion certain antigen-specific responses of the lymphatic immune system. In particular, subpopulations of the various T-cell types, including killer (or effector or cytotoxic) cells, helper cells, and suppressor cells are also activated by these tumors. As their names imply, the various subpopulations of T-cells exert effects on each other, presumably through soluble factors collectively known as lymphokines.
The suppressor subpopulation serves as a counterfoil to helper cells with respect to regulating the population of killer cells which are responsible for destroying the foreign material, in this case the tumor. The suppressor population has its own regulation. It appears that there are at least three levels of suppressor cells, each of which secretes one or more soluble (lymphokine) factors which influence other suppressor cells or the killer cell population directly. The mechanisms and materials involved in this cellular communication system are very far from understood, but a current model postulates that in response to stimulation by the antigen, an initial response is made by the secretion of "TsF.sub.1 " factors by T.sub.1 cells, which cells are classified as idiotypic since they are immunocomplementary to the initiating antigen. The TsF.sub.1 soluble protein factor(s) may in turn stimulate the secretion of TsF.sub.2 soluble protein factor(s) from T.sub.2 cells, which because they are presumably complementary to the idiotypic T.sub.1 receptors are classified as anti-idiotypes. The TsF.sub.2 factor(s) in turn may influence T.sub.3 cells and contrasuppressor cells, which are thought to have their own factors for communication. A diagramatic representation of this cascade postulated to account for findings thus far obtained is shown below: ##STR1##
As shown in the above figure, initial stimulation by the antigen produces TsF.sub.1 factor from T.sub.1 cells, which in turn stimulates T.sub.2 cells to secrete TsF.sub.2 factors which in turn influence Ts.sub.3 and contrasuppressor cells, which secrete their own factors for intercellular communication.
Some work has been done with respect to characterizing some of these cells and factors. A great aid in this work has been the availability of an antibody designated B16G which has been shown to be specific for murine T-suppressor cell factors, murine T suppressor cells, and human T-suppressor factors, but general among these --i.e., it seems to bind to all such factors regardless of their position in the cascade and regardless of the antigen employed to stimulate their secretion (Maier, T.A., et al J Immunol (1983) 131:1843; Steele, J.K., et al J Immunol (1985) 134:2767; and Steele, J.K., et al J Immunol (1985) 135:1201). The preparation of the B16G antibody was described by Maier, T.A., et al J Immunol (1983) (supra). This antibody is commercially available from QuadraLogic Technologies, Inc., Vancouver, British Columbia.
With the aid of this antibody as a screening tool, a number of soluble T-suppressors have been identified. Splenocytes and thymocytes in general appear to produce soluble suppressor factors which are immunoreactive with this antibody. In addition, stimulation of T.sub.1 cells in response to specific tumor antigens has permitted preparation of hybridoma cell lines which secrete factors in response to these antigens. For example, the A10 cell line is an immortalized T.sub.1 suppressor cell line obtained in response to P815 stimulation of murine DBA/2 thymocytes. The preparation of this cell line and characterization of the soluble factors it produces was described in Steele, J.K., et al J Immunol (1985) 134:2767 (supra). Analogous hybridoma cell lines have been produced by immortalization of suppressor-T cells obtained in response to injection of ferredoxin in vivo (Fd11; ) as described by Steele, J.K., et al J Immunol (1986) 137 (in press) A29 cells, a T.sub.2 type suppressor cell was obtained by immortalization of T cells of DBA/2 mice immunized with TsF.sub.1 preparations obtained from the ascites fluid from growth of the A10 cell line. The production of A29 cells is described by Steele, J.K., et al J Immunol (1986) 137 (in press).
Since the precise interrelationship of the soluble factors involved in the suppressor cascade is not at present known, effects of individual factors on the immune system of a subject mammal is to a large extent empirically derived. It has been disclosed that enhancement of the immune system is achieved by administration of a TsF.sub.2, as well as by administration of TsF.sub.1 factors if administered prior to exposure to a specific antigen against which the immune system is desired to be enhanced. If the TsF.sub.1 antigen is administered without adjuvant, the immune system enhancement is specific to the particular antigen with which the TsF.sub.1 administered was associated. Thus, it has been shown that when TsF.sub.1 obtained from A10 cells is injected without adjuvant into suitable murine subjects, later implantation of P815 tumors is accompanied by an immune response in these animals which exceeds that in animals which were not administered the TsF.sub.1 previously. However, syngenic but unrelated tumors, such as L1210 tumors are not affected by this treatment.
In short, preadministration in the absence of adjuvant of the TsF.sub.1 associated with a particular tumor type successfully immunizes the subject against that tumor, but not against unrelated tumors. See U.S. Pat. Ser. No. 025,463 filed 13 March 1987 incorporated herein by reference.
It has now been found that if the TsF.sub.1 factor preparation is administered prior to tumor implantation in the presence of adjuvant, not only is the animal immunized against growth of the related tumor, but against the growth of other tumors as well. Thus, administration of TsF.sub.1 factors in the presence of adjuvant seems to result in a general enhancement of the immune response.